The present invention relates to a method for increasing the oral bioavailability of eletriptan which comprises co-administering eletriptan with a p-glycoprotein (p-gp) inhibitor. The invention further relates to compositions and kits comprising eletriptan and a p-gp inhibitor.
Eletriptan is a potent and selective agonist for the vascular 5-HT1B and neuronal 5-HT1D receptors. Eletriptan causes selective constriction of intracranial vessels in the carotid distribution of animals, being more selective for the carotid distribution than for the coronary arteries. Although the precise cause and mechanism of migraine are not understood, a relationship between cranial blood vessels, which become dilated and inflamed in migraine, and the surrounding sensory nerves, is probably responsible. The resulting pain is thought to be an interaction between the distended blood vessels and the nerve fibres originating from the trigeminal ganglion. Eletriptan, a selective vasoconstrictor that is dosed orally, is therefore a convenient therapy for migraine.
Clinical trials using doses of 20, 40 and 80 mg show that the efficacy is increased and the time to abort a migraine attack is reduced with increasing dose level. Time to achieve effective plasma concentrations is reduced at the higher dose, while other factors, such as individual subject variability and environmental factors, are known to influence the rate and extent of exposure to eletriptan.
In vitro metabolism data indicate that eletriptan is predominantly metabolised by cytochrome P450-3A4 isozyme (CYP3A4). Therefore potent inhibition of this enzyme system by ketoconazole and erythromycin results in an increased systemic exposure and reduced clearance of eletriptan. The present invention is based, inter alia, on the results of a study to assess the safety, tolerability and pharmacokinetics of a single dose of eletriptan in the presence of a p-gp inhibitor, such as verapamil. Verapamil is a calcium ion influx inhibitor (xe2x80x98calcium channel blockerxe2x80x99) having both systemic and coronary arteriodilator activity which is mainly used for the control of angina pectoris and hypertension.
Verapamil is known to be a moderate inhibitor of CYP3A4 metabolising enzyme (Ki=10 xcexcM ), which is the primary route of systemic clearance for eletriptan. However, in vitro human liver microsomal studies indicated no verapamil effect on eletriptan metabolism (IC50 greater than 300 xcexcM). Verapamil is known to alter hepatic blood flow, which could also influence eletriptan pharmacokinetics, so hepatic blood flow was also evaluated in the study. The study was designed to provide additional clinical information on the effect of a moderate CYP3A4 inhibitor on eletriptan pharmacokinetics and help define the in vitro/in vivo drug interaction correlation. The study was to be used to provide information on the potential for pharmacokinetic interactions between eletriptan and other CYP3A4 inhibitors.
Accordingly, it would be advantageous to have a formulation of eletriptan which increased the drug""s oral bioavailability and thus could be dosed at lower doses and yet provide in a more consistent manner the efficacy benefits of a higher dose. An especially useful formulation could provide rapid onset and consistent action using a lower dose and reducing drug interactions and side-effects because of more consistent delivery. For example, a formulation which is, say, 50% more bioavailable could be dosed at 40 mg and provide the same systemic exposure as currently available formulations when dosed at 60 mg.
Certain excipients and drugs, when co-dosed with another drug, increase the oral absorption of that drug. Such excipients and drugs are thought to increase systemic exposure, at least in part, by inhibition of metabolism in the gut wall and liver and/or by inhibiting the p-gp/MDR efflux pumps found in the intestinal wall and other tissues. By way of further explanation, it is well known that a series of membrane proteins called Multi-Drug Resistance (MDR) proteins, which are heavily expressed in tumour cells, are able to excrete (or xe2x80x98pumpxe2x80x99) certain anticarcinogenic drugs out of tumour cells. A portion of the resistance which tumours develop toward chemotherapy is believed to be due to the action of these proteins, which pump drugs out of tumour cells before the drugs have an opportunity to affect the cell. In general, it is believed that the drug passively partitions across the cell plasma membrane to get into the cell and is actively transported out of the cell by MDR proteins. MDR proteins are also known as P-glycoproteins (p-gps).
P-gps are also present in many types of normal cells, including, as indicated, those of the intestinal epithelium. Intestinal epithelial cells (IECs) are polarized cells which line the intestinal wall, providing a barrier between the gastrointestinal tract and the blood. The apical side of the IEC faces the intestinal lumen and the basolateral side faces the portal blood. Most drugs are absorbed passively, first crossing the IEC apical cell membrane and entering the IEC interior, then crossing the basolateral cell membrane, thus exiting the cell on the basolateral side, entering the extracellular space and ultimately partitioning into the portal bloodstream. P-gps are located on the apical cell membrane of the IEC and have the capacity to pump certain drugs out of the IEC back into the intestinal lumen. Thus IEC p-gps hinder the absorption of many drugs. The p-gps in IECs may also have a role in presenting drugs to the drug metabolising enzymes; it has been speculated that their purpose is to slow or prevent oral absorption of toxins. The p-gp efflux pump belongs to the superfamily of ATP-binding cassette (ABC) membrane transport proteins.
P-gps exhibit low substrate specificity and transport many kinds of molecules. The specificity is not rigorously understood and there is presently no way of predicting from drug molecular structure whether a specific drug will be a substrate for intestinal p-gps. Thus it is generally not possible to predict whether a particular drug or compound will be subject to the efflux pumping action discussed above. Also, if a particular drug has low oral bioavailability, it is generally not possible to predict (1) whether the low bioavailability is caused, wholly or partially, by the efflux pumps discussed above, nor (2) whether the low bioavailability can be increased by co-administration of a p-gp inhibitor. It is unknown in the art whether the rate and extent of bioavailability of eletriptan (loge P0.5) can be improved by co-dosing eletriptan with another agent without also affecting systemic clearance.
European Patent Application No. 0742722 broadly claims, inter alia, a method for increasing the bioavailability of an orally administered hydrophobic pharmaceutical compound, for example, cyclosporine (loge P3.0), which comprises orally administering said compound concurrently with a bioenhancer comprising an inhibitor of a cytochrome P450-3 A enzyme or an inhibitor of p-gp-mediated membrane transport.
We have now surprisingly found that administering eletriptan with a p-gp inhibitor increases the rate of onset of migraine abortion without altering systemic drug clearance. The higher and more consistent bioavailability of eletriptan is also expected to attenuate the potential effects of any drug interactions.
Thus the invention provides eletriptan in combination with a p-gp inhibitor for use as a medicament by means of which the rate and extent of oral bioavailability of eletriptan are significantly improved.
The invention further provides for the use of eletriptan in the preparation of a medicament combined with a p-gp inhibitor for the treatment of migraine and for the use of eletriptan in the preparation of a medicament for the treatment of migraine for administration to patients concomitantly receiving a p-gp inhibitor. Pharmaceutical compositions comprising eletriptan and a p-gp inhibitor and kits comprising separate compositions of each are also provided.